HGG-11. GERMLINE GENETIC PREDISPOSITION TO PEDIATRIC GLIOMA. (23rd April 2019)

• Record Type: Journal Article
• Authors: Muskens, Ivo; Walsh, Kyle; Zhang, Chenan; Smith, Adam de; Morimoto, Libby; Ma, Xiaomei; Wiemels, Joseph
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 2
• Page Start: ii89
• Page End: ii89
• Publication Date: 2019-04-23
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz036.105
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: INTRODUCTION: Gliomas constitute a majority of pediatric brain tumors. While some advances have been made over recent years with regards to pediatric glioma etiology, most studies have evaluated a limited set of known cancer-predisposition genes. In the current study, the impact of rare germline variants on risk of pediatric glioma was evaluated in 320 patients (predominantly high-grade) derived with a population-based sampling strategy using whole-exome sequencing by evaluating 162 known cancer-related genes and by gene-burden testing. METHODS: DNA was extracted from neonatal dried blood spots from 320 pediatric glioma patients born and diagnosed in California and sequenced using the Personalis ACE whole-exome sequencing platform. 63 patients were diagnosed with a glioblastoma (GBM). Sequencing data were analyzed according to the Broad best practice guidelines. Variants with an allele frequency < 0.0001 in the Genome Aggregation Database (gnomAD) that were nonsense mutations, frameshift mutations, or mutations previously described in ClinVar as pathogenic were considered putatively causal. Additionally, gene-burden testing was performed for nonsense mutations, frameshift mutations, and mutations with a CADD score > 20 using gnomAD as a control dataset. RESULTS: All samples passed quality control and the mean read depth was 41.4. Thirty-one (9.7%) samples harbored a variant that was deemed putatively causal, of which 6 were located in TP53 . GBM patients harbored 4 of the TP53 mutations (6.4%). Gene-burden testing also revealed that the frequency of rare and predicted functional TP53 variants was significantly higher in pediatric glioma patients than in controls, reaching exome-wide significance ( p =2.87x10 -7 ). CONCLUSION: This study identified several putatively pathogenic germline mutations that may contribute to pediatric glioma risk. Variants in TP53 were associated with pediatric glioma on an exome-wide significance level, and most of these variants occurred in pediatric GBM patients. Pediatric GBM patients may, therefore, benefit from targeted sequencing of TP53 and adjusted treatment strategies.